Sitagliptin is chemically known as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine and represented as follows:

U.S. Pat. No. 6,699,871 discloses sitagliptin and describes the preparation of sitagliptin hydrochloride salt, while U.S. Pat. No. 7,326,708 claims the phosphate salt of sitagliptin or a hydrate thereof.
The key step in the synthesis of sitagliptin is the condensation of amino acid derivative with triazolo pyrazine compound. This being a peptide bond formation, according to the prior art, standard peptide coupling conditions and reagents are used.
Various patent applications such as WO2004087650, WO2009064476, WO2009084024, WO2010122578, WO2011102640, WO2011049344, WO2012025944 and WO2012042534, including U.S. Pat. No. 6,699,871, describe different methods of preparing sitagliptin and its pharmaceutically acceptable salts. However, all these applications describe the use of a standard peptide coupling agent with or without additive and in the presence or absence of a base for the condensation of the amino acid derivative with the triazolo pyrazine compound.
The common coupling reagents used are dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide (EDC), diisopropyl carbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI), carbonyldithiazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide, 1-tert-butyl-3-ethylcarbodiimide etc.
The common additives used are 1-hydroxy benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxysuccinimide etc.
These reagents are used widely in the synthesis of various products as they are cost effective and readily available.
However, these reagents do have certain disadvantages, such as:
1) the reaction is exothermic;
2) use of basic catalyst;
3) competitive hydrolysis of activated carboxyl group;
4) removal of dicyclohexyl urea byproduct obtained in DCC-HOBt mediated reaction;
5) the hazardous nature of the reagents such as HOBt;
6) the by-products of the reactions are toxic and hazardous in nature.
Further, the transportation and subsequent storage and use are critical issues for the reagents containing the imidazole ring benzotriazoles, e.g. HOBt, and for reagents with an extra nitrogen in the phenyl ring, e.g. HOAt. Recent studies have found that these compounds are unstable with relatively high sensitivity to friction, spark, and electrostatic discharge resulting in burning or explosion.
Carboxydiimides, for example, are well known for their skin irritating properties. In addition, prolonged use of benzotriazole based coupling reagents and additives (e.g. HOBt, HBTU, or TBTU) may not only cause skin irritation and contact dermatitis, but also sensitization and allergic reaction of the respiratory tract. In industry, these disadvantages are even more significant.
Thus the use of these reagents has been found to be incompatible and non-eco-friendly at industrial scale. Thus, there is a need to develop an industrially feasible, less hazardous and more eco-friendly process, which at the same time provides improved yield and chemical purity, as well as improved optical purity. The present invention therefore seeks to address these issues.